rs146908572

Variant names:

• chr22-21016091-A-T
• rs146908572
• NM_005446.5:c.314A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-21016091-A-T
• chr22-21016091-A-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001349876.2(P2RX6):​c.-64A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00011 in 1,561,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: P2RX6 NM_001349876.2 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.47
• Publications: 1 publications found

Genes affected

P2RX6 (HGNC:8538): (purinergic receptor P2X 6) The protein encoded by this gene belongs to the family of P2X receptors, which are ATP-gated ion channels and mediate rapid and selective permeability to cations. This gene is predominantly expressed in skeletal muscle, and regulated by p53. The encoded protein is associated with VE-cadherin at the adherens junctions of human umbilical vein endothelial cells. Alternative splicing results in multiple transcript variants. A related pseudogene, which is also located on chromosome 22, has been identified. [provided by RefSeq, Apr 2009]

P2RX6 Gene-Disease associations (from GenCC):

• myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000291240 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001349876.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX6	NM_005446.5	MANE Select	c.314A>T	p.Gln105Leu	missense splice_region	Exon 2 of 12	NP_005437.2	O15547-1
	P2RX6	NM_001349876.2		c.-64A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001336805.1
	P2RX6	NM_001349874.2		c.-132A>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001336803.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	P2RX6	ENST00000413302.7	TSL:1 MANE Select	c.314A>T	p.Gln105Leu	missense splice_region	Exon 2 of 12	ENSP00000416193.2	O15547-1
	P2RX6	ENST00000401443.5	TSL:1	c.236A>T	p.Gln79Leu	missense splice_region	Exon 2 of 12	ENSP00000385309.1	O15547-2
	P2RX6	ENST00000422210.5	TSL:1	n.299A>T		splice_region non_coding_transcript_exon	Exon 2 of 11	ENSP00000407920.1	H7C2V4

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000124 AC: 21 AN: 169224 AF XY: 0.000134

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.0000389

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000235

Gnomad OTH exome AF: 0.000435

GnomAD4 exome AF: 0.000110 AC: 155 AN: 1409146 Hom.: 0 Cov.: 31 AF XY: 0.000115 AC XY: 80 AN XY: 696272

African (AFR) AF: 0.0000624 AC: 2 AN: 32058

American (AMR) AF: 0.0000537 AC: 2 AN: 37222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25234

East Asian (EAS) AF: 0.00 AC: 0 AN: 36724

South Asian (SAS) AF: 0.0000125 AC: 1 AN: 79890

European-Finnish (FIN) AF: 0.0000200 AC: 1 AN: 50010

Middle Eastern (MID) AF: 0.000245 AC: 1 AN: 4086

European-Non Finnish (NFE) AF: 0.000129 AC: 140 AN: 1085660

Other (OTH) AF: 0.000137 AC: 8 AN: 58262

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74468

African (AFR) AF: 0.0000481 AC: 2 AN: 41570

American (AMR) AF: 0.0000653 AC: 1 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000158 Hom.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.0000770 AC: 9

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T
Eigen	Benign	0.14
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.5
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Benign	0.21
Sift	Benign	0.032	D
Sift4G	Uncertain	0.024	D
Polyphen		0.068	B
Vest4		0.58
MVP		0.19
MPC		0.13
ClinPred		0.75	D
GERP RS		4.2
Varity_R		0.29
gMVP		0.46
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.49		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.49		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146908572; hg19: chr22-21370380;